ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.3869C>T (p.Ser1290Leu)

gnomAD frequency: 0.00001  dbSNP: rs1031421025
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000534742 SCV000623320 uncertain significance Bloom syndrome 2022-10-30 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1290 of the BLM protein (p.Ser1290Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 454144). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BLM protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV001021321 SCV001182923 likely benign Hereditary cancer-predisposing syndrome 2018-10-17 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetic Services Laboratory, University of Chicago RCV001821469 SCV002070319 uncertain significance not specified 2020-08-19 criteria provided, single submitter clinical testing DNA sequence analysis of the BLM gene demonstrated a sequence change, c.3869C>T, in exon 20 that results in an amino acid change, p.Ser1290Leu. This sequence change does not appear to have been previously described in patients with BLM-related disorders. This sequence change has been described in the gnomAD database with a low population frequency of 0.0016% (dbSNP rs1031421025). The p.Ser1290Leu change affects a poorly conserved amino acid residue located in the helicase and RNaseD C-terminal domain of the BLM protein. The p.Ser1290Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ser1290Leu change remains unknown at this time.
GeneDx RCV002280123 SCV002568486 uncertain significance not provided 2022-02-23 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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